This invention relates to high drug load formulations, processes for preparing these formulations, and methods of using high drug load formulations in the treatment of certain disease states in mammals, in particular man. Specifically, the present invention relates to the use of anhydrous (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid in the preparation of high drug load immediate and modified release tablet formulations, wet or dry granulation processes for preparing high drug load granules, oral dosage forms containing these high drug load granules, and methods of using high drug load formulations of (E)-xcex1-[2-n-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid to block angiotensin II (AII) receptors and to treat hypertension, congestive heart failure and renal failure.
The compound, (E)-xcex1-[2-n-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid, is known by the name xe2x80x9ceprosartanxe2x80x9d and is the subject of U.S. Pat. No. 5,185,351 (the ""351 patent), issued Feb. 9, 1993. This patent discloses a process for making the anhydrous form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid and its methane sulfonate salt. Additionally, the ""351 patent discloses conventional techniques for formulating (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
International Application Number PCT/US97/04877, filed Mar. 26, 1997. relates to a novel dihydrated form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate, in particular, in pharmaceutical compositions for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure. This form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophene-propionic acid monomethanesulfonate is produced during the wet granulation of the anhydrous form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid monomethanesulfonate.
Surprisingly, it has been found that anhydrous (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid does not form a hydrate during wet granulation. This discovery has allowed for the preparation of reduced size, high drug load tablets. This is particularly important when formulating eprosartan for commercial use.
The present invention provides high drug load formulations of anhydrous (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid and oral solid dosage forms of this compound for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure. These high drug load formulations are in immediate or modified release oral solid dosage forms.
The present invention also provides processes for preparing high drug load tablet formulations of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]-methylene-2-thiophenepropionic acid by dry or wet granulation of the anhydrous form of (E)-xcex1-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid in the presence of pharmaceutically acceptable excipients.